1. Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites
Bioinformatics Vol. 21 no (Pages )
Reporter: Yu Lun Kuo (D )
Date: June 5, 2008

2. Motivation
3D structure are available for protein whose interaction with small molecules (ligands) are not known
Describe a new method of ligand binding site prediction called Q-SiteFinder
Use the interaction energy

3. Introduction Goal Applicat ion
Given a protein structure, predicts its ligand bindings
Flexible ligand docking
Lead optimisation
Applicat ion
Function prediction
Drug discovery
etc.

4. Docking Step

5. SURFNET

6. SURFNET

7. Introduction
Detection and characterization of functional sites on protein
Identify functional sites
In addition de novo drug design
Lead to the creation of novel ligands not found in molecular databases

8. Introduction The ligand binding site is usually in the largest pocket
SURFNET (Laskowski et al., 1996)
The ligand binding site was found to be in the largest pocket in 83% of cases
LIGSITE (Hendlich et al., 1997)
The ligand binding site was found in the largest pocket in all 10 proteins tested
etc.

9. Introduction Q-SiteFinder Defined only by energetic criteria
Calculates the van der Waals interaction energies of a methyl probe with the protein
Probes are ranked according to their total interaction energies

10. Introduction
Several techniques have been developed for estimating the interaction energy
GRID (Wade and Goodford)
Identify the hydrogen bonding potential of drug-like molecules
The interaction energies
Using a conventional molecular mechanics function
Van der Waals, electrostatic, and solvation terms

11. Introduction Q-SiteFinder
Keep the predicted ligand binding site as small as possible without compromising accuracy
Provide a threshold for success

12. Methods Datasets Consisted of 134 records obtained from the PDB
Correspond to the GOLD protein-ligand docking dataset (305 proteins)
Remove those with high levels of structural similarity
Which could bias the results
Solvent molecules were discarded
Phosphate, sulphate and metal ions
Q-SiteFinder is not designed to detect the binding site of small solvent molecules

13. Q-SiteFinder
Simply uses the van der Waals interaction (of a methyl probe) and an interaction energy threshold to determine favourable binding clefts

14. Results (Q-SiteFinder)
Define a successful prediction using a precision threshold
A threshold of 25% precision was used to define success in al the result here
A precision of 26% is considered a success
17% is not

15. Different Levels of Predicted Binding Site Precision
2gbp, 100% (Q-SiteFinder)
1bbp, 68%
(Q-SiteFinder)
1glq, 17%
(Q-SiteFinder).
1asc, 26% (Pocket-Finder)

16. Results (Q-SiteFinder)
If a ligand is successfully predicted in more than one site on a protein
It is counted as a success only in the higher ranking site
If more than one ligand is found in the same site
Only the success with the highest precision is counted for this site

17. Q-SiteFinder (Energy Threshold)
Success rate was 71% in the first predicted
Average precision was 68%
Precision of 0%
were excluded
First predicted binding site
It is desirable to have both a high rate of success
and a high precision of binding site prediction
a range of energy threshold values (−1.0 to −1.9 kcal/mol)

18. Results (Pocket-Finder)
Use a variable, MINPSP
PSP (protein-site-protein)
A pocket is identified if an interaction occurs followed by a period of no interaction, followed by another interaction
Measure the extent to which each grid point is buried in the protein
Each grid point has seven scanning lines passing through it
x, y and z direction and the four cubic diagonals

19. Results (Picket-Finder)
MINPSP (minimum number of PSP)
Thought of a burial threshold
PSP values for each grid point vary from 0 to 7
0: not a pocket
7: deeply buried

20. Pocket-Finder (PSP Threshold)
Success rate: 48%
Average precision: 29%
Best success rate

21. Results Hendlich et al. (1997) Our implementation of Pocket-Finder
Recommend a MINPSP of 2
Our implementation of Pocket-Finder
Low average precision: 8%
Large site volume: 8700 A3
(23% of the average protein volume)
No significant benefit in the success rate was observed on using a MINPSP of 2 rather than 5

22. Results Smaller sites have a higher average precision
Sites with high volume will usually incorporate locations on the protein surface
That are not part of binding site

23. Comparison Q-SiteFinder Pocket-Finder
Energy threshold value: -1.4 kcal/mol
Success rate: 71% average precision: 68%
At least one successful prediction in the
Top three predicted sites for 90% of the proteins
Top ten predicted sites for 96% of the proteins
Pocket-Finder
MINPSP threshold of 5
Success rate: 48% average precision: 29%
Top three predicted sites for 65% of the proteins
Top ten predicted sites for 74% of the proteins

24. Comparison of the success rates
Q-SiteFinder has a higher success rate in each of the top three predicted binding sites

25. Prediction in the first predicted site
Pocket-Finder detects a subset of the ligand binding sites
detected by Q-SiteFinder

26. Application of Q-SiteFinder
Success rate in the first predicted
Unbound state: 51%
Ligand-bound state: 80%
Q-SiteFinder for detecting binding sites on unbound protein
The average precision of the first predicted binding site
71% for the unbound state
74% for the ligand-bound state.
At least one success in the top 3
Unbound state: 86%
Ligand-bound state: 97%

27. Average Volume of Successfully Predicted Sites
Relax our threshold to allow any non-zero value (success requires a precision > 0%)
Average precision of
Pocket-Finder is 29%
Q-SiteFinder is 68%
Q-SiteFinder would appear to be more robust than Pocket-Finder,
and better able to pinpoint the location of the ligand binding site

28. Conclusion
Q-SiteFinder is better able to pinpoint the location of the ligand binding site than Pocket-Finder
High precision
Closely as possible to the actual binding site
Keep the predicted ligand binding site as small as possible without compromising accuracy
Given the high level of success in unbound protein sites
Do not have a ligand already bound

29. CHIME Interface

30. Java-Mage Interface

31. Reference Q-SiteFinder: Ligand Binding Site Prediction
Pocket-Finder: Pocket Detection

32. Thanks for your attention
2017/4/15